Benzothiazines in organic synthesis. The preparation of enantiomerically pure 4-substituted quinolones

3,4-Dihydroquinolin-2(1H)-ones have potential biological and pharmacological significance. Enantiomerically pure benzothiazines, readily available via an intramolecular addition of a sulfoximine-stabilized carbanion to an alpha,beta-unsaturated ester, could be used as templates for making a series of enantiomerically pure 3,4-dihydroquinolin-2(1H)-ones under mild conditions.     

Asymmetric synthesis of an enantiomerically pure rivastigmine intermediate using ketoreductase

A novel chemo-enzymatic synthesis of (S)-rivastigmine using ketoreductases with NADH/NADPH as the proton donor has been demonstrated. An exclusive enzymatic process has been developed by exploring the possible ketoreductases by screening to identify enzymes useful for the preparation of the (S)-isomer intermediate, and scaling up of the enzymatic process for the production of an adequate, enantiomerically pure precursor of rivastigmine and for the total synthesis of (S)-rivastigmine.     

Asymmetric synthesis via acetal templates. 12. Highly diastereoselective coupling reactions with a ketene acetal. An efficient,asymmetric synthesis of R-(+)-α-lipoic acid

TiCl₄ catalyzes the essentially quantitative coupling of chiral acetals $\text{1}$ with 1-$\text{t}$-butoxy-1-$\text{t}$-butyldimethylsilyloxyethene $\text{2}$ to generate β-alkoxycarboxylates in which the new asymmetric center is formed with excellent diastereoselection. β-hydroxycarboxylic acids of high ee result from removal of the chiral auxiliary. The procedure has been applied to the synthesis of R-(+)-α-lipoic acid $\text{10.}$     

Asymmetric synthesis via chiral acetal templates. 8. Reactions with organometallic reagents

The titanium tetrachloride catalyzed coupling of organometallic reagents with chiral acetals 1 is shown to provide a convenient route for the preparation of a variety of chiral alcohols 4 of high optical purity.     

Asymmetric synthesis of β-hydroxyacetamides mediated by enantiomerically pure sulphinyl derivatives

The aldol-type condensation of enantiomerically pure α-sulphinylacetamides is described. The stereochemical outcome of the reaction mainly depends on the nature of the base used to generate the enolate. Experimental evidences allow the identification of preferred reaction paths.     

Asymmetric synthesis of alpha,alpha-difluoro-beta-amino acid derivatives from enantiomerically pure N-tert-butylsulfinimines

Addition of the Reformatsky reagent derived from ethyl bromodifluoroacetate to alkyl- and aryl-substituted N-tert-butylsulfinimines furnishes beta-tert-butylsulfinamyl-beta-substituted alpha,alpha-difluoroproponiates in diastereomeric ratios ranging from 80:20 to 95:5. The diastereomers are easily separated and the enantiomerically pure, protected beta-amino esters are readily transformed to the corresponding acid, amide, and amine derivatives as useful synthons for medicinal chemistry targets.     

Asymmetric synthesis of β-hydroxythioacetamides mediated by enantiomerically pure sulphiny1 derivatives

Enantiomerically pure $\text{P}$-tolyl sulphinyl-N,N-dimethylthioacetamide (1) was prepared starting from (-)-(S)-menthyl toluene-$\text{p}$-sulphinate. Aldol-type condensation of (1) and subsequent removal of the Sulphinyl group open an entry to optically active β-hydroxy thioacetamides in 40–90% e.e.     

Asymmetric tandem additions to chiral 2-naphthyloxazolines. The synthesis of enantiomerically pure 1,2,2-trisubstituted- 1,2-dihydronaphthalenes

Addition of organolithium reagents to optically active 2-naphthyloxazolines followed by trapping with methyl iodide gives, after oxazoline removal, the titled compounds whose absolute configuration was determined by x-ray diffraction.     

Asymmetric synthesis of enantiomerically pure zingerols by lipase-catalyzed transesterification and efficient synthesis of their analogues

The achiral zingerone 1, readily available from ginger, can be easily transformed into chiral derivatives. Zingerol 2, a reduced product of zingerone 1 is expected to be an important new medicinal lead compound. We have achieved a concise synthesis of optically active zingerol (R)-2 and (S)-2 by the lipase-catalyzed stereoselective transesterification of racemic 2. Under the optimized conditions, a lipase from Alcaligenes sp. (Meito QLM) and vinyl acetate in i-Pr₂O or hexane at 35 °C within 1 h gave the alcohol (S)-2 and the acetate (R)-9 with high enantioselectivity without producing acetylated by-products. Since optically active (S)-2 and (R)-9 were obtained through lipase-catalyzed transesterification, other enantiomerically pure novel compounds could all be synthesized.     

Asymmetric synthesis via chiral acetal templates. 7. Further studies on the cyanation reaction. The use of acetals derived from diols with one chiral center

New examples of the cyanation reaction are described, including one that affords the cyanochydrin $\text{8}$, an intermediate for synthesizing pyrethroid insecticides. Also tile reaction with acetals derived from $\text{S}$-1,3-butanediol has been examined.     

Asymmetric synthesis of enantiomerically pure 7-isopropenyl-4a-methyl-3-methyleneoctahydrochromen-2-ones

Four stereoisomers of 7-isopropenyl-4a-methyl-3-methyleneoctahydrochromenon-2-one have been obtained for the first time. The key step of the synthesis involves asymmetric Michael addition of chiral enamines derived from dihydrocarvone to acrylate 1. Absolute configurations were established by X-ray analysis.     

Efficient synthesis of enantiomerically pure dihydropyrans

cis- and trans-2-Substituted-3,6-dihydro-2H-pyran-3-ols have been prepared via an aldol condensation/ring-closing metathesis/enzymatic resolution sequence. The process can be scaled up to yield gram quantities of enantiomerically pure material.     

Asymmetric synthesis of enantiomerically pure 4-aminoglutamic acids via methylenedimerization of chiral glycine equivalents with dichloromethane under operationally convenient conditions

We found that simple stirring of a biphasic mixture of the Ni(II) complex of glycine Schiff base 2 solution in dichloromethane with 30% aqueous NaOH in the presence of PT catalyst ⁿBu₄N⁺Br⁻ at room temperature for 24 h results in the formation of diastereo- and enantiomerically pure Ni(II) complex 3, containing (2S,4S) 4-aminoglutamic acid, in high chemical yield. The procedure described in this communication represents a synthetically efficient method for the asymmetric synthesis of 4-aminoglutamic acid on large scale.     

Efficient synthesis of enantiomerically pure beta2-amino acids via chiral isoxazolidinones

We report a practical and scalable synthetic route for the preparation of alpha-substituted beta-amino acids (beta(2)-amino acids). Michael addition of a chiral hydroxylamine, derived from alpha-methylbenzylamine, to an alpha-alkylacrylate followed by cyclization gives a diastereomeric mixture of alpha-substituted isoxazolidinones. These diastereomers are separable by column chromatography. Subsequent hydrogenation of the purified isoxazolidinones followed by Fmoc protection affords enantiomerically pure Fmoc-beta(2)-amino acids, which are useful for beta-peptide synthesis. This route provides access to both enantiomers of a protected beta(2)-amino acid.     

Carbocyclic Analogs of Nucleosides. Part 4. Preparation of enantiomerically pure analogs of purine nucleosides for the synthesis of sulfone-linked oligonucleotide analogs

Cyclopentane derivatives bearing a 3-(hydroxymethyl) group, a 4-(2-hydroxyethyl) functionality, and a nucleoside base are carbocyclic variants of nucleoside analogs previously described as building blocks for the preparation of oligonucleotide analogs having dimethylene sulfone (= methanosulfonylmethano) linking groups replacing the phosphodiester linking units found in natural oligonucleotides. These carbocyclic nucleoside analogs (e.g. 17 and 20 ) are stable to both acid-catalyzed depurination and base-catalyzed hydrolysis, in contrast with most non-ionic analogs of oligonucleotides. Furthermore, they can be prepared with complete control over the stereochemistry at the ‘anomeric’ center. A procedure is given for preparing these purine-nucleoside analogs via the construction of an enantiomerically pure carbocyclic skeleton (Schemes 1–3), followed by a Mitsunobu-type reaction to introduce the purine-base derivatives (Scheme 4). Furthermore, preliminary results for the coupling of these analogs to yield nucleoside dimers (e.g. 26 ) are also reported (Scheme 5).     

Asymmetric synthesis of (+)-allo-quercitol and (+)-talo-quercitol via free radical cycloisomerization of an enantiomerically pure alkyne-tethered aldehyde derived from a carbohydrate.

We describe for the first time the free radical cyclization of enantiomerically pure alkyne-tethered aldehydes obtained from a carbohydrate (6, 7). The synthesis of compounds 6 and 7 obtained from a derivative of D-ribose is reported. These radical precursors have been submitted to cyclization with tributyltin hydride plus azobisisobutyronitrile to yield, after ring closure, two carbocycles, respectively. These carbocycles have been obtained as mixtures of E and Z vinyltin isomers, but with excellent diastereoselection at the new stereocenter formed during the ring closure. After protodestannylation, only one diastereomer was detected and isolated. The absolute configuration at the new stereocenter formed during the carbocyclization has been established by detailed (1)H NMR analysis. The specific transformation of 7-methoxymethoxy-2,2-dimethyl-4-methylene-5-tert-butyldimethylsilyloxy-(3aR,5S,7S,7aS)-perhydrobenzo[d][1,3]dioxole into optically pure (+)-allo-quercitol and (+)-talo-quercitol is described. From these results, we conclude that under an appropriate choice of radical precursors and conditions, the synthesis of highly functionalized cyclohexane derivatives of biological interest is now available.     

Asymmetric synthesis via acetal templates. 9. Further studies of the allylation reaction. Preparation of (−)-dihydromyoporone

A procedure has been developed for the high-yield coupling of chiral acetals 1 with allyltrimethylsilane (2, R′=H) as well as with methallyltrimethylsilane (2,R′=ME) to afford the hydroxy ethers 3 in which the new chiral center is formed highly enantioselectively. Homoallylic alcohols 4 of high ee are produced by removal of the chiral auxiliary.     

The synthesis of diastereo- and enantiomerically pure beta-aminocyclopropanecarboxylic acids

The synthesis of diastereo- and enantiomerically pure beta-aminocyclopropanecarboxylic acids (beta-ACCs) is described. Starting from pyrrole, (rac)-4 is readily obtained, which was kinetically resolved by enzymatic hydrolysis. Subsequent oxidation of (-)-4 and deformylation gives rise to the cis-beta-ACC derivative (ent)-9, while (+)-10 was converted to the trans-beta-ACC derivative 8. Both 8 and (ent)-9 and their benzyl esters 13 and 16, being conformationally restricted beta-alanine or gamma-aminobutyric acid (GABA) derivatives, represent useful building blocks for peptides containing unnatural amino acids.     

Microwave assisted synthesis of enantiomerically pure allylboronates

Stable allylboronates with a stereogenic centre α to the boronic ester moiety represent versatile reagents for stereoselective synthesis of homoallylic alcohols. Use of microwave irradiation in desilylation and sigmatropic rearrangement reactions allows rapid synthesis of α-chiral allylboronates utilized in the highly diastereo- and enantioselective synthesis of (Z)-configured homoallylic α-hydroxy esters by allyl additions to ethyl glyoxylate.